title: HDAC dependent transcriptional repression of Bmp-7 potentiates TGF-β mediated renal fibrosis in obstructive uropathy.
abstract: OBJECTIVE
  Recombinant BMP-7 inhibits the pathogenesis of renal injury in response to various stimuli. However, little is known about the molecular regulation of endogenous BMP-7 and its renal protective functions. We examined transcriptional regulation of Bmp-7 and its role in the pathogenesis of renal injury resulting from urinary tract dysfunction.
  
  
  METHODS
  Obstruction induced renal injury was modeled in vivo in mice by unilateral ureteral obstruction and in vitro in primary kidney cells by treatment with transforming growth factor-β, a profibrotic cytokine that is increased in the obstructed kidney.
  
  
  RESULTS
  Unilateral ureteral obstruction resulted in the loss of BMP-7 expression in conjunction with histone deacetylation and transcriptional repression of the Bmp-7 promoter. The histone deacetylase inhibitor trichostatin A stimulated Bmp-7 expression in primary kidney cells. Trichostatin A also inhibited the expression of transforming growth factor-β dependent profibrotic genes in a manner that depended on BMP receptor signaling. These findings extended to the obstructed kidney in vivo, in which trichostatin A treatment restored the expression of Bmp-7 along with BMP-7 mediated suppression of transforming growth factor-β dependent signaling pathways. Finally, trichostatin A stimulated activation of the BMP-7 pathway the ameliorated obstruction induced renal injury by preventing disruption of the renal architecture and the development of renal fibrosis.
  
  
  CONCLUSIONS
  These findings show that histone deacetylase dependent repression of Bmp-7 transcription is a critical event during the pathogenesis of renal injury in obstructive uropathy. Accordingly, treatment with histone deacetylase inhibitors represents a potentially effective strategy to restore BMP-7 expression and its renal protective functions during treatment of obstructive uropathy.
authors.affiliation: Division of Urology, Department of Surgery and Division of Pediatric Nephrology, Departments of Medicine and Pediatrics (KAH), Washington University, St. Louis Children's Hospital, St. Louis, Missouri.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Manson
authors.affiliation: Division of Urology, Department of Surgery and Division of Pediatric Nephrology, Departments of Medicine and Pediatrics (KAH), Washington University, St. Louis Children's Hospital, St. Louis, Missouri.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Song
authors.affiliation: Division of Urology, Department of Surgery and Division of Pediatric Nephrology, Departments of Medicine and Pediatrics (KAH), Washington University, St. Louis Children's Hospital, St. Louis, Missouri.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Hruska
authors.affiliation: Division of Urology, Department of Surgery and Division of Pediatric Nephrology, Departments of Medicine and Pediatrics (KAH), Washington University, St. Louis Children's Hospital, St. Louis, Missouri. Electronic address: austinp@wustl.edu.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Austin
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis; D006655:Histone Deacetylases / Q000378:metabolism*; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000150:complications / Q000378:metabolism*
chemical_list: D055419:Bone Morphogenetic Protein 7; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D006655:Histone Deacetylases
keywords: BMP-7; COLIα1; ELISA; GAPDH; HDAC; IMCD; PCR; RT-PCR; SMA- and MAD-related protein; SMAD; TGF-β; TSA; UUO; bone morphogenetic protein 7; bone morphogenic protein 7; enzyme-linked immunosorbent assay; fibrosis; glyceraldehyde-3-phosphate dehydrogenase; histone deacetylase; histone deacetylase inhibitors; inner medullary collecting duct; kidney; polymerase chain reaction; reverse transcriptase-PCR; transforming growth factor-β; trichostatin A; type I collagen, α1 chain; unilateral ureteral obstruction; ureteral obstruction; α-SMA; α-smooth muscle actin